DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amendments and arguments filed on 02/26/2026 are acknowledged and have been fully considered. Claims 1-5 are cancelled. Claims 6, 7, 13, 19 and 21 are currently amended. Claims 6-22 are now pending will be examined on the merits herein.
Objections/Rejections Withdrawn
Objections and/or rejections not reiterated from previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6-12 are rejected under 35 U.S.C. 103 as being obvious over Gaglione, R et al., (Rosa Gaglione et al., Novel human bioactive peptides identified in Apolipoprotein B: Evaluation of their therapeutic potential, Biochemical Pharmacology, Volume 130, 2017, Pages 34-50, ISSN 0006-2952; published 25 January 2017) in view of de la Fuente (César de la Fuente-Núñez, et al., D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections, Chemistry & Biology, Volume 22, Issue 2, 2015, Pages 196-205,
ISSN 1074-5521; published 19 Feb 2015).
The applied references have a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). As such, the 102(b)(1)A exception does not apply without evidence to the contrary.
Claim 6 is directed to a method of treating a microbial infection comprising administering to a subject an effective amount of peptide of SEQ ID NO: 1.
Claim 7 is dependent on claim 6 and is directed to a method of treating a microbial infection which includes gram-negative bacteria.
Embodiments of the instant specification disclose microbial infection to be viral or bacterial. When the infection is viral, it may include any known viral pathogen. When the infection is bacterial, it may include gram-positive or gram-negative bacteria [0050]. ‘Effective amount’ as disclosed in the specification refers to amount of antimicrobial peptide that elicits a biological or medicinal response in a tissue, system, animal, individual or human [0040].
Gaglione, R teaches antimicrobial activity of peptide r(P)ApoBSPRO by measuring the MIC100 values on a panel of gram-negative and gram-positive bacterial strains (Table 3). Notably r(P)ApoBSPRO is endowed with a broad-range antimicrobial activity, being effective on both gram-positive and gram-negative bacterial strains. As shown in Table 3, E. coli ATCC 25922 and P. aeruginosa PAO1 are gram-negative strains. Gaglione, R teaches that bactericidal activity of the peptide, as indicated in kinetic killing curves (Fig 4b and 4d) demonstrate that 5-10 µM peptide concentration kills B. licheniformis cells within 10 min, while at 1.25-2.5 µM, killing is observed within 30 min (Section 3.4; Results).
Gaglione, R does not teach the reverse of r(P)ApoBSPRO peptide and replacing all (L) amino acids for their (D) counterparts.
De la Fuente teaches retro-inverso derivatives of antimicrobial peptides. Specifically, de la Fuente teaches that D-enantiomeric amino acids that replace the L-amino acid variant, exhibit protease resistant and anti-biofilm activity up to 10-fold more potent than previously identified antimicrobial peptides (Introduction, 4th paragraph). De la Fuente teaches that treatment of P. aeruginosa infected G. mellonella larvae with retro-inverso analog RI-1018 demonstrates antibiofilm activity as well as protects survival of the host (compared to the non-retro-inverso analog) indicating an advantage for the protease resistant variant (see Results; D-Enantiomeric peptides protected C. elegans and G. mellonella from lethal P. aeruginosa infections).
Consequently, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the antimicrobial peptide of Gaglione, R with the retro-inversion method of de la Fuente to produce a retro-inverso antimicrobial peptide to treat microbial infection. One motivated to do so would have a reasonable expectation of success as the retro-inversion of peptides is a known method to yield predictable results. Thus, one would have recognized that applying the teaching of Gaglione, R to the method of de la Fuente, would have yielded predictable results and improved the antimicrobial function, stability, protease resistant property and increased survival of infected host upon treatment with SEQ ID NO: 1 (See MPEP § 2143 I(D)).
Claims 8-12 is directed to treating microbial infection by administering the peptide of SEQ ID NO: 1 and additional antimicrobial agent, wherein the additional antimicrobial agent is an antibiotic and the antibiotic is active against bacterial membranes, bacterial cell wall and is an inhibitor of bacterial protein synthesis.
Embodiments of the specification disclose antibiotics that are active toward bacterial membranes (e.g., polymyxin B and colistin), antibiotics that inhibit protein synthesis (e.g., erythromycin, clindamycin and gentamicin) and antibiotics that target the bacterial cell wall (e.g., vancomycin) ([0057] line 16).
Gaglione, R teaches combination therapy for treating microbial infection with antimicrobial peptide r(P)ApoBSPRO in combination with antibiotics. Using the “chequerboard” experiment for calculation of a fractional inhibitory concentration (FIC) index, indications of “synergy” “additive” or “no interaction” effects are evaluated. Gaglione, R teaches that all combinations of peptide with antibiotic (Table 4), yields either synergistic or additive effects against Methicillin resistant S. aureus MRSA
WKZ-2, S. aureus ATTC 29213, P. aeruginosa ATCC 27853, P. aeruginosa PAO1, E. coli ATCC 25922. Notably the peptide is found to act synergistically with; (i) colistin on all the strains tested, except for S. aureus ATCC 29213; (ii) vancomycin on S. aureus MRSA WKZ-2, P. aeruginosa strains and E. coli ATTC 25922; (iii) erythromycin on P. aeruginosa ATCC 27853.
Gaglione, R, does not teach retro-inverso analog of r(P)ApoBSPRO peptide.
De la Fuente teaches retro-inverso derivatives of antimicrobial peptides with improved characteristics as detailed above.
Consequently, it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the peptide of Gaglione, R with the retro-inversion method of de la Fuente to produce a retro-inverso antimicrobial peptide in combination with antibiotics to treat microbial infection. One motivated to do so would have a reasonable expectation of success as the retro-inversion of peptides is a known method to yield predictable results. Thus, one would have recognized that applying the teaching of Gaglione, R, of using peptide in combination with antibiotics against microbial infection, to the retro-inverso method of de la Fuente, would have yielded predictable results and improved the antimicrobial method of treatment (See MPEP § 2143 I(D)).
Claims 13-18 are rejected under 35 U.S.C. 103 as being obvious over Gaglione, R (Rosa Gaglione et al., Novel human bioactive peptides identified in Apolipoprotein B: Evaluation of their therapeutic potential, Biochemical Pharmacology, Volume 130, 2017, Pages 34-50, ISSN 0006-2952; published 25 January 2017) in view of de la Fuente (César de la Fuente-Núñez, et al., D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections, Chemistry & Biology, Volume 22, Issue 2, 2015, Pages 196-205,
ISSN 1074-5521; published 19 Feb 2015).
Claims 13-18 is directed to a method of treating inflammation by administering the peptide of SEQ ID NO: 1 and additional antimicrobial agent, wherein the additional antimicrobial agent is an antibiotic and the antibiotic is active against bacterial membranes, bacterial cell wall and is an inhibitor of bacterial protein synthesis.
Embodiments of the specification do not disclose process steps for the method of treating inflammation to a subject in need thereof. Gaglione, R teaches that all combinations of peptide with antibiotic (Table 4), yields either synergistic or additive effects against Methicillin resistant S. aureus MRSA WKZ-2, S. aureus ATTC 29213, P. aeruginosa ATCC 27853, P. aeruginosa PAO1, E. coli ATCC 25922. Notably, Gaglione, R teaches the anti-inflammatory properties of r(P)ApoBSPRO by monitoring the effects on LPS induced interleukin-6 (IL-6) release, as well as on nitric oxide (NO) release in murine macrophages (RAW 264.7 cell line). It is known that, upon activation by internal and external stimuli, macrophages produce and secrete various endogenous inflammatory mediators, such as nitric oxide (NO) and pro-inflammatory cytokines, including interleukin-6. The effects of r(P)ApoBSPRO on the release of IL-6 is tested using ELISA assays on LPS stimulated RAW 264.7 cells. As shown in Fig 3a and b, a significant release of IL-6 is observed in control cells incubated with LPS from Salmonella Minnesota (50 ng/mL). Murine macrophages incubated with LPS (50 ng/mL) in the presence of r(P)ApoBSPRO (Fig 3b) peptide (two different peptide concentrations), demonstrate a strong decrease of IL-6 release compared to control cells. Macrophages pre-treated for 2 h with r(P)ApoBSPRO peptide and then incubated for further 24 h with LPS, demonstrate a significant decrease of IL-6 (Fig 3a and b). Gaglione, R teaches that similar results with the r(P)ApoBSPRO peptide are observed when the effects of ApoB derived
peptides are tested on NO release (Fig. 3c and d). Also in this case, following co-incubation of cells with LPS from Salmonella Minnesota and r(P)ApoBSPRO peptide, a significant attenuation of NO release with respect to control cells is detected (Fig 3c and d). Gaglione, R teaches that when RAW 264.7 cells are pre-treated for 2 h with 5 µM or 20 µM of r(P)ApoBSPRO peptide and subsequently stimulated for 24 h with LPS (50 ng/mL), a significant reduction of NO release is observed even at 5 µM peptide concentration (Fig 3c and d), confirming the protective effect of both peptides on LPS stimulated RAW 264.7 cells (Section 3.3; Results).
Gaglione, R does not teach retro-inverso analog of r(P)ApoBSPRO peptide.
De la Fuente teaches retro-inverso derivatives of antimicrobial peptides with improved characteristics as discussed above.
Consequently, it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the peptide of Gaglione, R with the retro-inversion method of de la Fuente to produce a retro-inverso antimicrobial peptide in combination with antibiotics to treat inflammation as claimed. One motivated to do so would have a reasonable expectation of success as the retro-inversion of peptides is a known method to yield predictable results. Thus, one would have recognized that applying the teaching of Gaglione, R, of using peptide in combination with antibiotics against inflammation, to the retro-inverso method of de la Fuente, would have yielded predictable results and improved the antimicrobial method of treatment (See MPEP § 2143 I(D)).
Claims 19-22 are rejected under 35 U.S.C. 103 as being obvious over Gaglione, R (Rosa Gaglione et al., Novel human bioactive peptides identified in Apolipoprotein B: Evaluation of their therapeutic potential, Biochemical Pharmacology, Volume 130, 2017, Pages 34-50, ISSN 0006-2952; published 25 January 2017) in view of de la Fuente (César de la Fuente-Núñez, et al., D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections, Chemistry & Biology, Volume 22, Issue 2, 2015, Pages 196-205,
ISSN 1074-5521; published 19 Feb 2015).
The applied references have a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). As such, the 102(b)(1)A exception does not apply without evidence to the contrary.
Claims 19 and 20 are directed to a method of contacting biofilm with effective amount of peptide of SEQ ID NO: 1 wherein the biofilm comprises gram-negative bacteria.
Claims 21 and 22 are directed to a method of reducing biofilm formation on a surface comprising contacting the surface with peptide of SEQ ID NO: 1 and wherein the biofilm comprises gram-negative bacteria.
The instant specification does not disclose a special definition for the term “surface”. The broadest reasonable interpretation consistent with the ordinary and customary meaning of the term and consistent with the specification and drawings, is interpreted as a solid or liquid material that supports biofilm formation.
Regarding claims 19 and 20, Gaglione, R teaches contacting r(P)ApoBSPRO with preformed biofilms. Gaglione, R teaches that preformed biofilms of E. coli ATCC 25922 (Fig 5c) and S. aureus MRSA WKZ-2 (Fig 5f) strains treated with increasing concentrations of r(P)ApoBSPRO (Fig 5c, f), demonstrate about 50% reduction in biofilm. Biofilm reduction is observed in P. aeruginosa PAO1 strain (Fig 6f). For biofilms formed by P. aeruginosa ATCC 27853 about 20% reduction is observed (Fig 6c).
Regarding claims 21 and 22, Gaglione, R teaches a method for reducing biofilm formation by diluting the anti-biofilm peptide r(P)ApoBSPRO in BM2 medium containing increasing concentrations of the peptide and bacteria. Gaglione, R teaches a dose-dependent (of peptide) inhibition of biofilm formation in the case of E. coli ATCC 25922 (Fig 5b) and S. aureus MRSA WKZ-2 (Fig 5e) strains treated with r(P)ApoBSPRO (Fig 5b, e) peptides. R(P)ApoBSPRO also affects P. aeruginosa PAO1 biofilm formation (Fig 6e). In the case of P. aeruginosa ATCC 27853, instead, a less pronounced effect (about 20% biofilm formation inhibition) is observed (Fig 6b).
Gaglione, R does not teach retro-inverso analog of r(P)ApoBSPRO peptide.
De la Fuente teaches retro-inverso derivatives of antimicrobial peptides with improved characteristics as detailed above.
Consequently, it would be prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the peptide of Gaglione, R with the retro-inversion method of de la Fuente to produce a retro-inverso antimicrobial peptide for reducing biofilm formation. One motivated to do so would have a reasonable expectation of success as the retro-inversion of peptides is a known method to yield predictable results. Thus, one would have recognized that applying the teaching of Gaglione, R, of using peptide against biofilms formed from gram-negative bacteria, to the retro-inverso method of de la Fuente, would have yielded predictable results and improved the method of reducing biofilm formation (See MPEP § 2143 I(D)).
Response to Arguments
Applicant’s arguments filed 02/26/2026 have been fully considered but they are not persuasive.
Applicant argues that the prior art references do not present a prima facie case of obviousness; the evidence of record does not demonstrate that those of ordinary skill in the art would have had a reasonable expectation that it would be possible to enhance or even conserve antimicrobial activity of a
peptide as a result of modifying it by both (i) retro-inverso (RI) conversion and (ii) L-to-D substitution. However, the rejection of record was that it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Gaglione, R and de la Fuente. One would have been motivated to do so with a reasonable expectation of success as both are directed towards antimicrobial peptides intended to work on bacterial infections, biofilm, inflammation. The combined prior art, i.e. Gaglione, R and de la Fuente, teach microbial infection, inflammation and biofilm, in the context of the inventive concept of the instant application: i) Gaglione, R teaches antimicrobial activity on a panel of gram-negative and gram-positive bacterial strains. In Table 3, E. coli ATCC 25922 and P. aeruginosa PAO1 are gram-negative strains. Kinetic killing curves using the peptide are demonstrated on Bacillus licheniformis ATCC21424 and E. coli ATTC 25922 (Fig 4b and 4d). ii) Gaglione, R teaches combinations of peptide with antibiotic (Table 4), yield either synergistic or additive effects against Methicillin resistant S. aureus MRSA WKZ-2, S. aureus ATTC 29213, P. aeruginosa ATCC 27853, P. aeruginosa PAO1, E. coli ATCC 25922. iii) Gaglione, R teaches r(P)ApoBSPRO with preformed biofilms of E. coli ATCC 25922 (Fig 5c) and S. aureus MRSA WKZ-2 (Fig 5f) (Fig 5c, f) and P. aeruginosa PAO1 (Fig 6f). For biofilms formed by P. aeruginosa ATCC 27853 about 20% reduction is observed (Fig 6c). iv) Gaglione, R teaches the anti-inflammatory properties of r(P)ApoBSPRO by monitoring the effects on LPS induced interleukin-6 (IL-6) release, as well as on nitric oxide (NO) release in murine macrophages (RAW 264.7 cell line). See Fig 3a and b; Fig. 3c and d; Section 3.3; Results.
Applicant has submitted a Declaration Under 37 C.F.R. § 1.132 of Dr. César de la Fuente-Núñez (the "de la Fuente-Núñez Declaration"), in which the declarant, who represents a highly skilled person in the present field with direct responsibility for the work described in the 2015 article, explains how the cited reference does not establish a general rule that L-to-D or retro-inverso conversion renders peptides functionally interchangeable with their parent forms (de la Fuente-Núñez Declaration at 1 8).
Applicant argues that the 2015 article does not support a reasonable expectation that a particular prior-art peptide, once converted to a D- or retro-inverso form, would retain (much less improve) antimicrobial or antibiofilm function. The Examiner would like to remind the Applicant that the burden is on the Applicant to establish results are unexpected and significant. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
“[E]evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967) (resultant decrease of dental enamel solubility accomplished by adding an acidic buffering agent to a fluoride containing dentifrice was expected based on the teaching of the prior art); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARCHANA VARADARAJ whose telephone number is (571)272-2366. The examiner can normally be reached Monday-Friday 10:00am-5:00pm.
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/ARCHANA VARADARAJ/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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